chapter 13 antineoplasticdrugs.ppt

Chapter 13 Antineoplastic Agents Malignant tumor is a serious threat to human health and the frequently-occurring diseases, the human death caused by malignant tumors is the second place among the death of all disease. Therapy ： Surgical operation Radiation therapy Chemical treatment Antineoplastic agents aim at anti-malignant tumor, also known as anti- cancer drugs. Classification by mechanism 1. Alkylating agents 2. Antimetabolites 3. Drugs intefering with synthesis of protein of tumor cells 13.1 Biological alkylating agents 1.Nitrogen mustards 2.Ethylene imines 3.Sulfonates and halogenated polyols 4.Nitrosourea Bioalkylating agents are cytotoxic drugs. In vivo, it is able to form a positive charged carbon-ion or other active electrophilic groups, and then the electrophilic ions combine covalently with electron rich groups (such as amino, sulfhydryl, hydroxyl, carboxyl, phosphate, etc.) of the cells of biological macromolecules (DNA, RNA, enzymes), lead to the breaking of DNA molecule, at last result in the death of tumor. However, bioalkylating drugs also inhibit the normal cells with the property of rapid proliferation such as bone marrow cells, intestinal epithelial cells at same time. So the bioalkylating agents have more serious side effects, such as nausea, vomiting, bone marrow suppression and hair loss. Clinical usually are carrying on combined use with other drugs. Biological alkylating agents General formula of nitrogen mustards （1）Fraction of alkylation is anti-tumor function group, existing as bis- -chloro-ethylamine. （2）Fraction of carrier：可以改善药物药代动力学性质，选用不同 载体，可提高选择性和抗肿瘤活性。依据载体化学结构，可分为脂 肪氮芥、芳香氮芥、氨基酸氮芥、杂环氮芥和甾体氮芥。 13.1.1 Nitrogen mustards Mechlorethamine hydrochloride N-甲基-N-（2-氯乙基）-2-氯乙胺盐酸盐 N-methyl-N-(2-chloroethyl)-2-chloroethylamine hydrochloride Clinical application: mainly treatment for lymphosarcoma and Hodgkins disease Development: during the First World War, nitrogen mustard was used as a toxic gas, shortly after it was found the property of inhibiting bone marrow and lymphoid tissue of the victims. In 1942, Gilman from Yale University firstly used nitrogen mustard in the treatment of lymphoid neoplasms. Different R：脂肪氮芥、芳香氮芥 Alkylation process: 脂肪氮芥的氮原子碱性比较强，烷基化历程是双分子亲核取 代反应，活泼的乙撑亚胺离子极易与细胞成分的亲核中心起 烷化作用，属强烷化剂。 It is usually used as injection drug of aqueous solution, which pH value maintained at 3.0 5.0. Stability ： Chlormethine hydrochloride presented strong destruction to tumor cells, but with poor selectivity and large toxicity. Only Effective for lymphoma, so structural modification is necessary. Nitromin: Reduced the possibility of formation of ethylene imine for the reduced electronic cloud on nitrogen. Nitromin is less toxicity, but also the reduced anti-tumor activity. N CH3 Cl Cl O 2. Aromatic nitrogen mustards: The introduction of aromatic ring led to reduction of alkalescence by reason of conjugation, so mechanism was changed, no formation of cyclic ethylene imine ion but the formation of carbon cation intermediate. Cyclophosphamide P-N，N-双-（-氯乙基）-1-氧-3-氮-2-磷杂环己烷-P-氧化 物一水合物。 With a broad spectrum of anti-tumor。 Physicochemical properties of cyclophosphamide White crystal or crystalline powder (失去结晶水 即液化) Soluable in water, unstable in aqueous solution and easily hydrolyze, easily decompose under heating condition. Cyclophosphamide is a prodrug.在肝脏被活化， 经非酶促的-消除反应生成丙烯醛（膀胱毒性） 、磷酰氮芥及去甲氮芥，三者都是较强的烷化剂 。 Cyclophosphamide has a broad spectrum of anti-tumor, clinical for treatment of malignant lymphoma, acute lymphocytic leukemia, multiple myeloma, lung cancer etc. Clinical application of cyclophosphamide 以二乙醇胺作为原料，用过量的三氯氧磷同时进行氯代和磷酰化 ，制得氮芥磷酰二氯，再与3-氨基丙醇缩合。 Synthesis of cyclophosphamide 美法仑 Melphalan 氮芥类的烷化剂，结构包括氮芥和L-苯丙氨酸部分，氮芥部分在碱性水溶液中 易水解，含有氨基酸结构，会发生茚三酮显色反应，且有氨基酸两性性质 。 氮芥类药物是通过在体内转变成乙撑亚胺中间 体发挥烷化剂作用，乙撑亚胺的磷酰胺衍生物 ，可提高抗肿瘤作用及减小毒性。 Tepa was clinical used for treatment of leukaemi。 Thiotepa changed into tepa in vivo. Clinical for the treatment of breast cancer, ovarian cancer, bladder cancer, and so on. 13.1.2 Ethylene imines Tepa Thiotepa Sulfonates and halogenated polyols are non-nitrogen mustard alkylating agents。甲磺酸酯是较好的离去基团，生成碳正离 子与生物大分子发生亲核取代反应进行烷基化。Busulfan,also known as Myleran, named as:4-Butanediol dimethyl sulfonate 。Clinical for the treatment of chronic myeloid leukemia. 多元醇类药物主要是卤代多元醇，进入体内后会形成双环氧化 物而产生烷化作用。二溴甘露醇(Dibromomannitol)、二溴卫矛 醇(Dibromodulcilol)等。 13.1.3 Sulfonates and halogenated polyols 13.1.4 Nitrosoureas N-亚硝基的存在使该氮原子与邻近羰基之间的键变得不稳定，在 体内分解生成亲电性基团，破坏DNA的结构。 Nitrosoureas are highly lipophilic, easily pass through the blood- brain barrier for treatment of brain tumors, central nervous system tumors and malignant lymphoma, but with side effects of delayed bone marrow suppression. Clinical used drugs includes Carmustine（卡莫司汀）， Lomostine (洛莫司汀)， Semustine( 司莫司汀)， Nimustine(尼莫司汀) and so on. 卡莫司汀 Carmustine N，N-双（-氯乙基)-N-亚硝基脲，又名卡氮芥 N, N-bis-(-chloroethyl)-N-nitrosourea Carmustine is highly lipophilic, easily pass through the blood-brain barrier for the treatment of brain tumors, other central nervous system tumors and malignant lymphoma. Synthesis of Carmustine 13.2 Antimetabolites Interfere with pyrimidine, purine and folic acid for biosynthesis of DNA of tumor cells, so inhibiting metabolism of tumor cell, at last leading to the death of tumor cell. Classification of antimetabolites 1. pyrimidines 2. purines 3. Folic acids 尿嘧啶掺入肿瘤组织的速度较其他嘧啶快，氟的原子半径与氢 的原子半径相近，氟化物的体积与原化合物几乎相等，CF键 的稳定性在代谢过程中不易分解。氟尿嘧啶能在分子水平代替 正常代谢物，欺骗性地掺入生物大分子，导致“致死合成”。 Fluorouracil can replace normal metabolites at the molecular level, deceptively incorporated of biological macromolecules, resulting in “Synthesis of death.“ 5-氟尿嘧啶，5-fluorouracil, 5-FU 5-氟-2,4（1H, 3H）-嘧啶二酮 5 - fluoro -2,4 (1H, 3H) - pyrimidine-dione 13.2.1 Pyrimidines 本品抗瘤谱比较广，对绒毛膜上皮癌及恶性葡萄胎有显著疗效，对结肠癌、 直肠的癌、胃癌等有效，是治疗实体肿瘤的首选药。 Fluorouracil has broad spectrum of anti-tumor, significant effective to choriocarcinoma and malignant mole, effective to colorectal cancer, rectal cancer, stomach cancer, is the first choice for the treatment of solid tumor. Clinical application of Fluorouracil Synthesis of fluorouracil 巯嘌呤 Mercaptopurine 6-Mercaptopurine monohydrate 用于各种急性白血病的治疗，对绒毛膜上皮癌及恶性葡萄胎也有效。 For the treatment of a variety of acute leukemias, also effective to chorionic epithelial cancer and malignant mole. 磺巯嘌呤钠增加了药物的水溶性。遇酸性和巯基化合物均易 释放出6-MP，对肿瘤组织有一定的选择性。 Tisupurine is more water-soluble than mercaptopurine (6- MP). Easily release 6-MP under acidic condition or the existing of sulfhydryl compounds, has selectivity to tumor tissue. 磺巯嘌呤钠 Tisupurine Synthesis of tisupurine 盐酸阿糖胞苷 Cytarabine hydrochloride 1-D-呋喃型阿拉伯糖胞嘧啶盐酸盐 1-D-arabinofuranosyl cytosine hydrochloride 用于治疗急性粒细胞白血病。 Clinical mainly for the treatment of acute myeloid leukemia. Metabolism and stability: 盐酸阿糖胞苷会迅速被肝脏 中的胞嘧啶脱氨酶作用脱氨，生成无活性的尿嘧啶阿 糖胞苷，故口服吸收较差，通常是通过静脉连续滴注 给药。 Prodrugs of cytarabine: 为了减轻体内的脱氨失活，将 其氨基酰化成前药，如依诺他滨、棕榈酰阿糖胞苷， 抗肿瘤活性强而持久。 甲氨蝶呤 methotrexate 4-4(2,4-二氨基-6-蝶啶）-甲基-N-甲胺基-苯甲 酰基-L-谷氨酸 4 - 4 (2,4 - diamino -6 - Pteridinyl) -methyl-N- methylamino - benzoyl-L-glutamaic acid 甲氨蝶呤是叶酸的拮抗剂，对二氢叶酸还原酶的亲和力比二氢叶 酸强1000倍，几乎是不可逆地和二氢叶酸还原酶结合，使二氢叶 酸不能转化为四氢叶酸，从而影响辅酶F的生成，抑制DNA和RNA 的合成。 Methotrexate is an antagonist of folic acid, the affinity to dihydrofolate reductase is 1000 times stronger than dihydrofolate, almost irreversibly combined with dihydrofolate reductase, so that dihydrofolate can not be transformed into tetrahydrofolate, so methotrexate interfere with the generation of coenzyme F, inhibiting the biosynthesis of DNA and RNA of tumor cells. For treatment of acute leukemia, chorion cell carcinoma and malignant mole. 强酸条件下不稳定，酰胺键水解，生成谷氨酸和蝶呤酸而 失去活性。 Bleomycin, seperated from streptomyces verticillus. Broken the DNA chains to kill tumor by acting on tumor cell directly. 13.3 Natural antitumor agents 13.3.1 Anti-tumor antibiotics 多个氨基酸的N孤对电子对体内铜、铁、锌等形成1：1配合物，配合物转化为 过渡态的活性物，DNA断裂。二噻唑部分嵌入DNA与特定部位结合，使DNA 裂解。 13.3.2 Topoisomerase inhibitors Camptothecins act on DNA topoisomerase (Topo ), effective to digestive tract tumor. 10-羟基喜树碱(hydroxy camptothecin) 喜树碱是从中国特有的珙桐科植物喜树中分离得到的第一个内酯生物碱， 羟基喜树碱是喜树碱的羟基衍生物，由五个环稠和而成，A、B环是喹啉环 ，C环为吡咯环，D环为吡啶酮结构，E环是一个-羟基内酯环。共有两个氮 原子：一个是内酰胺的氮原子，一个是喹啉的氮原子，碱性较弱，与酸不 能形成稳定的盐。 Camptothecin is a DNA topoisomerase inhibitor, its anti-cancer mechanism is not due to inhibition of enzyme activity, but by blocking the last step reaction between enzyme and DNA, leading to DNA breakage and cell death. 放线菌D （更生霉素）(dactinomycin) Dactinomycin is the embedded topoisomerase inhibitor. 13.3.3 Topoisomerase inhibitors 阿霉素（多柔比星）(doxorubicin) Doxorubicin is an anthraquinone anti -tumor antibiotic, a general antineoplastic agent. orange needle crystal, stable in aqueous solution and instable under alkaline condition and be easy to decompose, with side effect of bone marrow suppression and cardiac toxicity. Mechanisms: embedded topoisomerase inhibitor, embedding among DNA molecules. Nonembedded ToPoinhibitor : 切断DNA双链，不嵌入. podophyllotoxin Mechanism:作用于微管蛋白外，还干扰蛋白质代谢 Clinical application:for the treatment of acute and chronic leukemia. 长春花生物碱类 紫杉醇 taxol 紫杉烷类广谱的抗肿瘤药物 Mechanism: 具有聚合和稳定微管的作用，有丝分裂抑制剂. Clinical application:for the treatment of ovarian cancer and breast cancer. 顺铂 Cisplatin In 1969, P